As described in United States Provisional Patent Application No. 60/565,269, an endogenous brain protein, Neuropeptide S (NPS) which is believed to affect arousal, wakefulness, propensity for movement, asthma and some allergic responses, stress associated with several anxiety disorders and other physiological functions. Human NPS (hNPS) has the following amino acid sequence: Ser-Phe-Arg-Asn-Gly-Val-Gly-Thr-Gly-Met-Lys-Lys-Thr-Ser-Phe-Gln-Arg-Ala-Lys-Ser-OH (SEQ ID NO:1). It is now available commercially as product No. E010051 from PentaBiotech, Inc., Union City, Calif.
Neuropeptide S is the endogenous ligand for the Neuropeptide S receptor (NPSR), which has also been referred to as TGR23 and vasopressin receptor-related receptor 1 (VRR1) (Genbank accession no. BD183774, BD183814, BD183773). The NPSR is a G protein coupled receptor (GPCR).
NPS acts as an agonist of the NPSR, causing dose dependent intracellular Ca++ mobilization as well as adenyl cyclase accumulation measured by cAMP assay. NPS is also involved in G protein-coupled receptor for asthma susceptibility. Y. L. Xu, R. X. Reinscheid, S. Huitron-Resendiz, S. D. Clark, Z. Wang, S. H. Lin, F. A. Brucher, J. Zeng, N. K. Ly, S. J. Henriksen, L. d'Lecea, O. Civelli, Neuron, 43, 487-497 (2004).
PCT International Patent Publication WO 02/31145 A1 (Sato) describes certain functions of NPS and the NPSR. However, PCT International Patent Publication WO 02/31145 A1 (Sato) does not describe specific pharmacological characteristics and physiological functions of the GPCR system, NPS, the NPSR or its amino acid sequence (Genbank accession no. BD183774, BD183814, BD183773). PCT International Patent Publication WO 02/31145 A1 (Sato) is expressly incorporated herein in its entirety.
PCT International Patent Publication WO 2005/021555 A1 (Takeda Pharmaceutical Company) described certain bicyclic piperazine compounds that a NPSR antognists and are purportedly useable in the prevention and treatment of certain cancers. PCT International Patent Publication WO 2005/021555 A1 (Takeda Pharmaceutical Company) is expressly incorporated herein by reference.
Definitions
When used in this patent application, the following terms and abbreviations shall be interpreted as follows:
The verb “to treat” and formatives/tenses thereof (i.e., treats, treating, treatment, etc.) shall include therapeutic, preventative, paliative, experimental and diagnostic treatments.
The term “subject” shall include human and other animal patients and non-patient subjects who receive therapeutic, preventative, experimental or diagnostic treatment, humans and animals who have a disease or are predisposed to a disease and/or laboratory animals or humans who on whom tests or experiments are performed.
Compositions or methods “comprising” one or more recited elements may include other elements not specifically recited. For example, a composition that comprises NPS may encompass both an isolated NPS of human or animal origin as a component of a larger polypeptide sequence or as part of a composition or preparation that includes other pharmacologically active or inactive ingredients or components.
The term “Isolated” means purified, substantially purified or partially purified. Isolated can also mean present in an environment other than a naturally occurring environment. For example, NPS that is not present in or mixed with nervous tissue, extracellular fluid, cerebrospinal fluid of other body fluids/tissues in which NPS would ordinarily be found when naturally occurring shall be deemed to be isolated NPS.
The verb “to administer” and formatives/tenses thereof (i.e., administers, administering, administration, etc.) shall include any act of providing or delivering a substance to a human or animal subject or to in vitro preparation, including but not limited to oral, enteral, intravenous, intraarterial, parenteral, subcutaneous, intradermal, transdermal, transmucosal, buccal, sublingual, lingual, rectal, intraperitoneal, central, intraventricular, intrathecal, epidural, spinal, topical, alveolar, inhalational, transtracheal and all other routes by which such substance may be administered or provided. Additionally, acts that cause, induce, stimulate, accelerate, enhance or facilitate the biosynthesis or endogenous production of an endogenous naturally occurring substance (e.g., endogenous NPS) shall also be construed as acts of “administering” such substance. Additionally, acts that inhibit, decrease, slow, interfere with or block the metabolism and/or clearance of a naturally occurring substance (e.g., endogenous NPS) so as to result in the presence of increased or greater amounts of the substance within the body of a human or animal subject shall also be construed as acts of “administering” such substance.
The acronym “NPS” shall mean “neuropeptide S”, including those of human and animal origin having the amino acid sequences shown in FIG. 1.
The acronym “hNPS” shall mean “human neuroeptide S”, the amino acid sequence of which is: Ser-Phe-Arg-Asn-Gly-Val-Gly-Thr-Gly-Met-Lys-Lys-Thr-Ser-Phe-Gln-Arg-Ala-Lys-Ser-OH (SEQ ID NO: 1).
The acronym “NPSR” shall mean “neuropeptide S receptor” or “TGR23” or “vasopressin receptor-related receptor 1.”
The acronym “WT” shall mean “wildtype.”
The acronym “GPCR” shall mean “G protein-coupled receptor.”
The acronym “SNP” shall mean “single nucleotide polymorphism.”
The acronym “MAPK” shall mean “mitogen-activated protein kinase.”
The acronym “LC” shall mean “locus coeruleus.”
The acronym “Ala” or the symbol “A” shall mean “Alanine.”
The acronym “Arg” or the symbol “R” shall mean “Arginine.”
The acronym “Asn” or the symbol “N” shall mean “Asparagine.”
The acronym “Asp” or the symbol “D” shall mean “Aspartic Acid.”
The acronym “Asx” or the symbol “B” shall mean “Asparagine or Aspartic Acid.”
The acronym “Cys” or the symbol “C” shall mean “Cystine.”
The acronym “Gln” or the symbol “Q” shall mean “Glutamine.”
The acronym “Glu” or the symbol “E” shall mean “Glutamic Acid.”
The acronym “Glx” or the symbol “Z” shall mean “Glutamine or Glutamic Acid.”
The acronym “Gly” or the symbol “G” shall mean “Glycine.”
The acronym “His” or the symbol “H” shall mean “Histidine.”
The acronym “Ile” or the symbol “I” shall mean “Isoleucine.”
The acronym “Leu” or the symbol “L” shall mean “Leucine.”
The acronym “Lys” or the symbol “K” shall mean “Lysine.”
The acronym “Met” or the symbol “M” shall mean “Methionine.”
The acronym “Phe” or the symbol “F” shall mean “Phenylalanine.”
The acronym “Pro” or the symbol “P” shall mean “Proline.”
The acronym “Ser” or the symbol “S” shall mean “Serine.”
The acronym “Thr” or the symbol “T” shall mean “Threonine.”
The acronym “Trp” or the symbol “W” shall mean “Tryptophan.”
The acronym “Tyr” or the symbol “Y” shall mean “Tyrosine.”
The acronym “Val” or the symbol “V” shall mean “Valine.”Additional terms, acronyms and/or symbols are defined elsewhere in this patent application.